Journal article
HELQ promotes RAD51 paralogue-dependent repair to avert germ cell loss and tumorigenesis
Cancer Research UK1
Department of Systems Biology, Technical University of Denmark2
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark3
Cancer Systems Biology, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark4
University of Zurich5
Dana-Farber Cancer Institute6
Repair of interstrand crosslinks (ICLs) requires the coordinated action of the intra-S-phase checkpoint and the Fanconi anaemia pathway, which promote ICL incision, translesion synthesis and homologous recombination (reviewed in refs 1, 2). Previous studies have implicated the 3'-5' superfamily 2 helicase HELQ in ICL repair in Drosophila melanogaster (MUS301 (ref. 3)) and Caenorhabditis elegans (HELQ-1 (ref. 4)).
Although in vitro analysis suggests that HELQ preferentially unwinds synthetic replication fork substrates with 3' single-stranded DNA overhangs and also disrupts protein-DNA interactions while translocating along DNA, little is known regarding its functions in mammalian organisms. Here we report that HELQ helicase-deficient mice exhibit subfertility, germ cell attrition, ICL sensitivity and tumour predisposition, with Helq heterozygous mice exhibiting a similar, albeit less severe, phenotype than the null, indicative of haploinsufficiency.
We establish that HELQ interacts directly with the RAD51 paralogue complex BCDX2 and functions in parallel to the Fanconi anaemia pathway to promote efficient homologous recombination at damaged replication forks. Thus, our results reveal a critical role for HELQ in replication-coupled DNA repair, germ cell maintenance and tumour suppression in mammals.
Language: | English |
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Publisher: | Nature Publishing Group |
Year: | 2013 |
Pages: | 381-384 |
Journal subtitle: | International Weekly Journal of Science |
ISSN: | 14764687 and 00280836 |
Types: | Journal article |
DOI: | 10.1038/nature12565 |
Animals Carcinogenesis DNA Damage DNA Helicases DNA Repair DNA Replication Fancd2 protein, mouse Fanconi Anemia Fanconi Anemia Complementation Group D2 Protein Female Gene Deletion Germ Cells HELQ protein, mouse Male Mice Multiprotein Complexes Ovarian Neoplasms Ovary Rad51 Recombinase Rad51 protein, mouse Recombinational DNA Repair